2. Academic Validation
  3. Development of selective small molecule MDM2 degraders based on nutlin

Development of selective small molecule MDM2 degraders based on nutlin

  • Eur J Med Chem. 2019 Aug 15:176:476-491. doi: 10.1016/j.ejmech.2019.05.046.
Bo Wang 1,  Suzhen Wu 2,  Jin Liu 1,  Ka Yang 1,  Haibo Xie 1,  Weiping Tang 3
Affiliations

Affiliations

  • 1 School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA.
  • 2 School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA; Gannan Medical University, Ganzhou, Jiangxi Province, 341000, PR China.
  • 3 School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53705, USA. Electronic address: [email protected].
PMID: 31128449 DOI: 10.1016/j.ejmech.2019.05.046
Abstract

Tumor suppressor protein p53 is important to the regulation of many cellular processes and the prevention of Cancer development. In some Cancer cells, the function of p53 is inhibited by murine double minute 2 protein (MDM2). To restore the function of p53, the inhibition or depletion of MDM2 has become a potential therapeutic treatment. We have successfully developed a series of small molecule MDM2 degraders that can promote the proteolysis of MDM2 oncoprotein, thus reactivating tumor suppressor p53. The superior degrader features a nutlin-based MDM2 ligand and a lenalidomide-based Cereblon E3 ubiquitin Ligase ligand with a short linker between the two ligands. At low nanomolar concentrations in RS4; 11 leukemia cells, this degrader promotes efficient degradation of MDM2. It also inhibits the proliferation of leukemia cells with an IC50 value of 3.2 nM and induces Apoptosis effectively. All of these data indicate that MDM2 degraders are promising therapeutics for the treatment of cancers, such as leukemia.

Keywords

Degraders; Induced protein degradation; MDM2; PROTACs; p53.

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